Troglitazone use in insulin-treated type 2 diabetic patients. The Troglitazone Insulin Study Group.

OBJECTIVE: To determine the ability of troglitazone to reduce requirements for injected insulin while maintaining blood glucose levels in insulin-treated patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This 26-week double-blind study with open-label extension included patients who had failed previous oral antidiabetic medication and took > or =30 but <150 U of insulin daily The 222 patients in the double-blind study received 200 or 400 mg troglitazone once daily or matching placebo. The primary end point was the proportion of patients meeting the target of > or =50% reduction in injected insulin and either a 15% reduction in fasting blood glucose or a blood glucose <7.8 mmol/l. Insulin dose was reduced 25% based on a study-specific algorithm whenever fasting blood glucose was reduced 5% from baseline. Also of interest were changes in insulin dose and HbA1c. The open-label extension included 173 patients. They received 200 mg of troglitazone with optional titration to 400 mg, and insulin dose was adjusted based on investigators' standards of care. Open-label measures were change in insulin dose, HbA1c, and fasting serum glucose (FSG). RESULTS: In the double-blind phase, 22 and 27% of the 200- and 400-mg troglitazone groups, respectively, reached target, compared with placebo (7%) (P < 0.01). Insulin dose reductions of 13 +/- 3, 30 +/- 3, and 41 +/- 3 U were observed for placebo, 200-, and 400-mg troglitazone groups, respectively HbA1c decreased 0.09 +/- 0.14% for placebo, 0.13 +/- 0.14% for 200 mg, and 0.41 +/- 0.14% for 400 mg (P < 0.05) troglitazone. In the open-label extension, troglitazone treatment resulted in >50% reduction from baseline in daily insulin dose and decreases in HbA1c of 1% and in FSG of >17%. CONCLUSIONS: Troglitazone decreases daily injected insulin dose requirements and improves glycemic control in insulin-treated patients with type 2 diabetes.

Nonpressor mechanisms in CNS-induced natriuresis.

Ventriculocisternal perfusion was performed in pentobarbital-anesthetized dogs. Perfusion of high Na (300 mM NaCl) artificial cerebrospinal fluid (CSF) (E) for 2 h was preceded by 2 h of control (C) and was followed by 2 h of recovery (R) during which normal (150 mM NaCl) artificial CSF was perfused. A time-control group was perfused with normal artificial CSF throughout C, E, and R. High sodium perfusion resulted in a marked natriuresis in each of nine animals and suppression of plasma renin activity. Theere were no simultaneous changes in mean arterial pressure, glomerular filtration rate, or renal plasma flow. Sodium excretion and plasma renin activity showed a slight gradual rise in the time-control group, but no significant differences were observed between the C and E periods; sodium excretion and plasma renin activity were similar in the high Na and time-control groups during C and R, but significantly different during E. It is concluded that when CSF sodium is elevated by perfusing artificial CSF, the resulting natriuresis and suppression of plasma renin activity are not caused by hemodynamic changes.

CI-926 (3-[4-[4-(3-methylphenyl)-1-piperazinyl]butyl]-2,4-imidazolinedione): antihypertensive profile and pharmacology.

CI-926 (10(-7)-10(-6) M) selectively antagonized the contraction of isolated rabbit aortae to phenylephrine and displaced the alpha-1 adrenoceptor ligand WB4101 (IC50: 82 nM) in rat brain. In the spontaneously hypertensive rat, single oral doses of either CI-926 (0.3-10 mg/kg) or prazosin (0.3-100 mg/kg) caused dose-related reductions in blood pressure; however, CI-926 was more efficacious. The maximal antihypertensive response to CI-926 was unchanged with three consecutive days of oral dosing in the spontaneously hypertensive rat, whereas a first dose effect was noted with prazosin. In two-kidney, one-clip, renal hypertensive rats, CI-926 and prazosin (1-10 mg/kg) lowered blood pressure; however, prazosin was more efficacious. In perinephritic hypertensive dogs, CI-926 (10 mg/kg) lowered blood pressure 20%. In anesthetized dogs, CI-926 in the presence of supermaximal blood pressure-lowering doses of prazosin caused an additional reduction in pressure. With equivalent alpha-1 blockade in anesthetized rats, CI-926 tended to have greater hypotensive activity than prazosin. These results demonstrate that CI-926 is a potent, orally active antihypertensive agent in renin-dependent and -independent hypertension. The profile of CI-926 suggests that it lowers blood pressure in part by interacting with peripheral alpha-1 adrenoceptors and in part via an additional mechanism(s). Although weak relative to its affinity for alpha-1 adrenoceptors, CI-926 was found in preliminary experiments to interact with alpha-2 adrenoceptors, serotonergic receptors and dopaminergic receptors. The importance of these interactions to the blood pressure response of CI-926 remains to be elucidated.